THE EXPANDING GENETIC HORIZONS OF PRIMARY ALDOSTERONISM

Transcription

1 THE EXPANDING GENETIC HORIZONS OF PRIMARY ALDOSTERONISM Silvia Monticone 1, Fabrizio Buffolo 1, Martina Tetti 1, Franco Veglio 1, Barbara Pasini, Paolo Mulatero 1 1 Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Via Genova, 1, Torino, Italy. Division of Medical Genetics, Department of Medical Sciences, University of Torino, Italy. Corresponding author: Paolo Mulatero, MD, Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Via Genova, 1, Torino, Italy. paolo.mulatero@unito.it Phone: +0 Fax: +01 Short title: Genetics of primary aldosteronism Word count: abstract 1; manuscript (without references and figure captions) (with references and figure captions) Key words: primary aldosteronism, familial hyperaldosteronism, aldosterone producing adenoma, KCNJ, ATP1A1, ATPB, CACNA1D, CACNA1H, CTNNB1, APCC 1

2 Study Country Families (n) Patients (n) Sex (M/F) Hypertension (n/tot available) Spontaneous hypokalemia Low renin / elevated ARR Elevated hybrid steroids Reported symptoms / TOD / CV events / other Before the identification of the CYPB1/CYPB chimeric gene Sutherland 1 (1) CANADA 1 /0 / / / n.a. Headache, LVH, retinopathy, death due to cerebrovscular events in siblings of the index case New 1 () USA 1 1 1/0 1/1 1/1 1/1 n.a. Polyuria, polidipsia, enuresis, headache, LVH, retinopathy. Miura 1 () JAPAN 1 1 0/1 1/1 1/1 1/1 n.a. Headache, retinopathy. Born form consanguineous hypertensive parents Giebink 1 () USA 1 /1 / / / n.a. Headache, polyuria, nicturia, retinal arteriolar spasms, LVH. History of cerebral hemorrhage at young age (maternal grandmother) Grim () USA (Dutch Indonesian origin) 1 /0 / 0/ / n.a. LVH New () USA / / n.a. / n.a. Ganguly () USA 1 1/ / / / n.a. Easy fatiguability, muscle cramps and carpopedal spasms, dizziness, exertional dyspnea, headache. One family member died of cerebral hemorrhage at the age of 1, one of myocardial infarction at the age of Oberfield () USA 1 / / n.a. / n.a. n.a. Lee 1 () MEXICO 1 1 1/0 1/1 1/1 1/1 n.a. n.a. Fallo 1 () ITALY 1 /1 / / / n.a. The father of the index cases died of stroke at the age of 0 Woodland 1 () AUSTRALIA /0 / / / n.a. One patient had strong family history of hypertension; the other was an adopted child

3 Connell 1 (1) UK 1 /0 / 1/ / / n.a. Davis 1 (1) UK 1 /0 / 1/ / / The mother of the index case had a cerebrovascular event at the age of O Mahony 1 (1) IRELAND 1 /0 / / / n.a. Strong family history of premature cardiovascular death Yamakita 1 (1) JAPAN n.a. 1 / /1 /1 1/1 n.a. Retinopathy Total 1 /0 /1 (%) /0 (%) 1/1 (0%) / After the identification of the CYPB1/CYPB chimeric gene Study Country Families (n) Patients (n) Sex (M/F) Hypertension (n/tot available) Spontaneous hypokalemia Low renin / elevated ARR Elevated hybrid steroids Reported symptoms / TOD / CV events / other Rich 1 (1) USA 1 1 / /1 1 * /1 # /1 1/1 Prevalence of iuretic induced hypokalemia %. High prevalence of cerebrovascular events in young age as cause of death Comiter 1 (1) USA 1 1 0/1 1/1 0/1 1/1 1/1 Family history of early onset hypertension and death for cerebrovascular events at young age in / 1 st and nd degree relatives Jamieson 1 (1) UK 1 / 1/1 /1 1/1 n.a. n.a. Pascoe 1 (1) FRANCE 1 / / n.a. n.a. n.a. n.a. Gates 1 (0) USA 0 1/1 /0 /1 n.a. n.a. LVH, retinopathy. Family history of cerebral haemorrhage Hsieh 1 (1) CHINA 1 1 n.a. n.a. n.a. n.a. n.a. n.a.^ Litchfield 1 () USA 1 /0 / n.a. n.a. n.a. 1 cerebrovascular events in 1 patients with proven GRA Stowasser 000 () AUSTRALIA 1/1 n.a. / 1/0 1/1 Family history of stroke in some of the families Gates 001 () UK 1 / / / n.a. n.a. Family history of cerebral haemorrhage at young age Yokota 001 () JAPAN 1 0/ / 0/ / n.a. General fatigue, pregnancy induced hypertension. History of not fatal stroke Ding 00 () CHINA 1 / / / / n.a. Headache, muscle weakness, flaccid paralysis, tatany,

4 nicturia, palpitation, stroke in one patient Mulatero 00 () ITALY 1 1 /1 /1 0/1 1/1 1/1 No history of stroke in the affected family members Fallo 00 () ITALY 1 /1 / 1/ 1/ / LVH Vonend 00 () GERMANY 1 /0 / 0/ / / Microalbuminuria Lee 0 (0) KOREA 1 /1 / 0/ / n.a. Two cerebral aneurysms in the same patient Aglony 0 (1) CHILE ^ ^ / / / / n.a. 1 cerebellar stroke Mulatero 0 () ROMANIA 1 1/1 / 0/ / n.a. Family history of aortic dissection at young age / / / / / 1 cerebral aneurysm, family history of stroke SCOTLAND Kamrath 0 () 1 Carvajal 01 () CHILE 1 /1 1/ 1/ / / Total 0 1/1 1/ /1 (1%) / (0%) / (%) Supplemental table S1. Main clinical and biochemical features of patients affected by Familial Hyperaldosteronism type I before and after the identification of the CYPB1/CYPB chimeric gene. Hypertension was defined according to the 01 ESH guideline ; hypokalemia was defined as serum K + <. mmol/l; low renin was defined as PRA < 1 ng/ml/h (1. pmol/l/min) ; elevated ARR was defined as > 0 ng*dl - 1 /ng*ml -1 *h -1 (0 pmol*l -1 /pmol*l -1 *min -1 ) TOD = target organ damage; CV events = cardiovascular events; LVH = left ventricular hypertropy. * spontaneous hypokalemia was reported at diagnosis of hypertension, but the patient was found to be normokalemic at further evaluations; # one patient had normal PRA (.0 ng/l*s) under treatment with K + sparing diuretic; full text not available in English; ^ compared to the original manuscript, one family and three patients have been omitted since they are included in Carvajal 01 ().

5 Supplemental references Sutherland DJ, Ruse JL & Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. The Canadian Medical Association Journal New MI & Peterson RE. A new form of congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism (doi:.1/jcem---00). Miura K, Yoshinaga K, Goto K, Katsushima I, Maebashi M, Demura H, Iino M, Demura R & Torikai T. A case of glucocorticoid-responsive hyperaldosteronism. Journal of Clinical Endocrinology and Metabolism 1 -. (doi:.1/jcem--1-). Giebink GS, Gotlin RW, Biglieri EG & Katz FH. A kindred with familial glucocorticoid suppressible aldosteronism. Journal of Clinical Endocrinology and Metabolism (doi:.1/jcem---1). Grim CE & Weinberger MH. Familial, dexamethasone-suppressible, normokalemic hyperaldosteronism. Pediatrics -0.. New MI, Oberfield SE, Levine LS, Dupont B, Pollack M, Gill JR Jr & Bartter FC. Autosomal dominant transmission and absence of HLA linkage in dexamethasone suppressible hyperaldosteronism. Lancet Ganguly A, Grim CE, Bergstein J, Brown RD & Weinberger MH. Genetic and pathophysiologic studies of a new kindred with glucocorticoid-suppressible hyperaldosteronism manifest in three generations. Journal of Clinical Endocrinology and Metabolism 0-. (doi:.1/jcem---0). Oberfield SE, Levine LS, Stoner E, Chow D, Rauh W, Greig F, Lee SM, Lightner E, Witte M & New MI. Adrenal glomerulosa function in patients with dexamethasone-suppressible hyperaldosteronism. Journal of Clinical Endocrinology and Metabolism 1-1. (doi:.1/jcem--1-1)

6 Lee SM, Lightner E, Witte M, Oberfield S, Levine L & New MI. Dexamethasone suppressible hyperaldosteronism in a child with nephrosclerosis. Acta Endocrinologica (Copenh) Fallo F, Sonino N, Armanini D, Luzzi T, Pedini F, Pasini C, Mantero F. A new family with dexamethasone-suppressible hyperaldosteronism: aldosterone unresponsiveness to angiotensin II. Clinical Endocrinology (Oxf) Woodland E, Tunny TJ, Hamlet SM, Gordon RD. Hypertension corrected and aldosterone responsiveness to renin-angiotensin restored by long-term dexamethasone in glucocorticoidsuppressible hyperaldosteronism. Clinical and Experimental Pharmacology and Physiology Connell JM, Kenyon CJ, Corrie JE, Fraser R, Watt R, Lever AF. Dexamethasonesuppressible hyperaldosteronism. Adrenal transition cell hyperplasia? Hypertension Davis JR, Burt D, Corrie JE, Edwards CR, Sheppard MC. Dexamethasone-suppressible hyperaldosteronism: studies on overproduction of 1-hydroxycortisol in three affected family members. Clinical Endocrinology (Oxf) O'Mahony S, Burns A, Murnaghan DJ. Dexamethasone-suppressible hyperaldosteronism: a large new kindred. Journal of Human Hypertension Yamakita N, Yasuda K, Noritake N, Mercado-Asis LB, Murase H, Mune T, Morita H, Miura K. Study on clinical and endocrine characteristics of dexamethasone-suppressible hyperaldosteronism compared with those in primary aldosteronism owing to aldosteroneproducing adenoma. Acta Endocrinologica (Copenhagen) Rich GM1, Ulick S, Cook S, Wang JZ, Lifton RP & Dluhy RG. Glucocorticoid-remediable aldosteronism in a large kindred: clinical spectrum and diagnosis using a characteristic biochemical phenotype. Annals of Internal Medicine

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